Project Summary/Abstract Prenatal alcohol exposure (PAE) can produce dramatic effects on brain, cognition, and facial morphology (BCF). Fetal alcohol spectrum disorder (FASD) is preventable, yet remains among the top 3 known causes of intellectual disability. The large variability in PAE-effects on BCF associations likely results, in part, from variability in maternal alcohol consumption patterns including quantity, frequency and timing (QFT) and early life experience. Both stigma and retrospective assessment of maternal alcohol consumption patterns during pregnancy have made it difficult to accurately understand what patterns of PAE are most harmful to development. Most children with FASD experience greater early life adversity than non-exposed children, but existing research on how PAE impacts brain development has not been able to disentangle the impact of early life adversity. Early intervention is believed to be key in attenuating PAE-effects, and may depend, in part, on understanding the impact of QFT and early life experience. In this proposal, we aim to better understand how QFT of PAE plus early life experience impact brain and cognitive development. Most prospective studies of PAE have recruited samples biased towards moderate-heavy PAE, limiting our understanding of the entire range of PAE patterns including minimal exposure. Here we capitalize on a unique prospective, community sample of approximately 6,000 South African children whose mothers reported on drinking behavior during pregnancy as part of the Prenatal Alcohol, SIDS and Stillbirth (PASS) Network. Thus, we are in an exceptional position to understand how QFT of PAE independently, or interactively, impacts associations between: 1) brain and cognition; 2) brain and early life environment; and 3) brain and facial morphology as function of environmental/maternal factors. 400 PASS participants (300 PAE/100 non-exposed Controls; 50% girls) aged 8-10 years at enrollment, will undergo multi-modal neuroimaging to assess A) structural MRI measures of brain volume, thickness and surface area; B) diffusion imaging of underlying white matter microstructure (i.e., structural connectivity); and C) resting state functional MRI (i.e., functional connectivity). Measures of cognition will utilize the NIH Toolbox Cognition Battery, and early life experience will be measured for maternal (i.e., age, nutrition, parity, mental health, co-substance use, parenting style, parent-child closeness) and environmental (i.e., multiple measures of SES, access to resources, stress) risk factors, measured both perinatally and during childhood. Quantitative measures from 3D facial imaging will be utilized in parallel with neuroimaging and cognitive assessments. Utilizing the entire range of PAE, we expect independent and interactive (e.g., quantity by timing, etc.) effects of QFT on BCF associations, with the largest effects driven by quantity, followed by frequency, and then timing of PAE. For example, we expect to see PAE-effects among children with very low exposure throughout pregnancy in more lateral brain regions (develop later in utero), whereas binge-like high exposure in early pregnancy will show more midline brain anomalies (develop earlier in utero).